Prostaglandin D2 is a known agonist of the thromboxane A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently identified G-protein-coupled “chemoattractant receptor-homologous molecule expressed on Th2 cells” (CRTH2).
The response to allergen exposure in a previously sensitized host results in a cascade effect involving numerous cell types and release of a number of cytokines, chemokines, and multiple mediators. Among these critical initiators are the cytokines interleukin (IL)-4, IL-13, and IL-5, which play critical roles in Th2 cell differentiation, immunoglobulin (Ig)E synthesis, mast cell growth and differentiation, upregulation of CD23 expression, and the differentiation, recruitment, and activation of eosinophils. The stimulated release of the array of mediators, causes end-organ damage, including constriction and hyperresponsiveness, vascular permeability, edema, mucous secretion, and further inflammation.
Because of the number of responses targeted, corticosteroids have proven to be the most effective therapy. Rather than antagonizing these specific responses in a directed way, another approach is to alter the immune response, that is, to change the nature of the immunological response to allergen. CRTH2 is preferentially expressed on Th2 cells and is a chemoattractant receptor for PGD2 that mediates PGD2-dependent migration of blood Th2 cells. Chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation and may provide the conceptual basis for the development of new therapeutic strategies, especially in allergic conditions.
So far, few compounds having CRTH2 antagonistic activity have been reported in the patent literature. Bayer AG claims in GB Patent Specification No. 2 388 540 the use of Ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid) for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjuvatitis (see also Journal of Pharmacology and Experimental Therapeutics (2003), 305(1), 347-352, wherein a certain oral bioavailability of Ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported). Further, (2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid and (2-ethoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid are disclosed by Kyle F. et al in two patent specifications i.e. in U.S. Pat. No. 5,817,756 and WO 95/07294, respectively.
More recently, certain 1-carboxymethyl-indole derivatives of the formula
wherein R1 can notably be hydrogen, halogen or C1-6 alkyl, R2 can notably be hydrogen and R3 is optionally substituted aryl or heteroaryl, have been disclosed. These compounds are presented as being active on the CRTH2 receptor and therefore potentially useful for the treatment of various respiratory diseases.